title: Association of the GNAS locus with severe malaria.
abstract: Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case-control studies from The Gambia, Kenya and Malawi, and a case-control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association (P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05-1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81-0.96), P = 0.005 and OR = 1.12 (1.03-1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK. sa3@sanger.ac.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakite
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Fry
authors.forename: Anita
authors.initials: A
authors.lastname: Ghansah
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.forename: Fatou
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Griffiths
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Kwadwo A
authors.initials: KA
authors.lastname: Koram
authors.forename: Abraham R
authors.initials: AR
authors.lastname: Oduro
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Kasturi
authors.initials: K
authors.lastname: Haldar
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000349:Africa; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000097:blood / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008288:Malaria / Q000097:blood / Q000235:genetics* / Q000469:parasitology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs